An understanding of the mechanism of action of antiarrhythmic drugs requires that the factors responsible for the arrhythmias be understood. The objectives of the proposed research are to gain a more complete insight into: 1) the electrophysiologic factors, particularly slowed conduction, involved in arrhythmia production, 2) the precise correlation between the metabolic consequences of ischemia and these electrophysiologic abnormalities, 3) the relationships between changes in the single cell and changes in the intact heart and 4) the influence of antiarrhythmic drugs on the metabolic and electrophysiologic changes. To accomplish these objectives we propose studying single fibers and intact hearts utilizing microelectrodes, His bundle and intramyocardial recording techniques. We will also utilize ion specific microelectrodes to determine changes in ionic activities within the interstitial space induced by ischemia. To model ischemia for single fiber studies, we will superfuse the preparation with solutions in which K is increased, pO2 and pH are decreased and glucose is omitted. In the intact heart we will study the effects of systemic and coronary hyperkalemia on conduction velocity and its determinants. In both single fiber and intact heart experiments we will determine the effects of antiarrhythmic drugs on the effects of the various interventions. It is hoped that the proposed study will contribute to our ability to treat and prevent cardiac arrhythmias.